This application proposes to investigate cellular and molecular changes in chronic nerve compression (CNC) injuries, such as carpal tunnel syndrome, cubital tunnel syndrome, and spinal nerve root stenosis. These localized, peripheral neuropathies produce pain, altered sensation, and motor atrophy in millions of Americans each year. However, knowledge about the cascade of cellular and molecular events leading to injury is limited, as are the number of effective treatments for CNC patients. Our previous work suggests that axonal pathology is absent in the early phases of CNC injury, unlike with acute neural injuries; we recently reported that CNC injury induces both Schwann cell proliferation and apoptosis, with minimal detectable axonal pathology. We also reported that CNC injury provides a slow, sustained stimulus for macrophage recruitment, which differs from Wallerian degeneration's immediate signal for macrophage recruitment. These findings suggest that CNC injuries have a fundamentally distinct pathogenesis compared with acute nerve injuries. Building on our existing work, this application will assess the level of axonal sprouting with the Schwann cell proliferation of CNC injury, evaluate how the early Schwann cell changes after CNC injury directly alter neurophysiology, determine the extent of macrophage recruitment and its effect on Schwann cell proliferation, and define the role of mechanical stimulation on Schwann cell proliferation and axonal sprouting.